The Modulation Effects Of Losartan On Fear Processing

Fear is an evolutionary highly conserved emotion,which serves a crucial role to facilitate survival and adaptive functioning across species.However,maladaptive and dysregulated fear responses and fear learning critically contribute to the development and maintenance of fear-related disorders including anxiety disorder and post-traumatic stress disorder(PTSD).Exposure-based interventions that capitalize on fear extinction learning mechanisms are currently the most efficient interventions for long-term treatment success in fear-related disorders,however,the efficacy of exposure-based interventions is critically impeded by the fact that these disorders are characterized by marked impairments in extinction learning,leading to slow treatment success,high drop-out rates and spontaneous re-emergence of fear after successful extinction.As such,innovative strategies to enhance fear extinction,which in turn could improve the efficacy or shorten the duration of exposure therapies,are urgently needed.Although translational research has previously identified a number of potentially promising pharmacological neuroenhancers(e.g.,d-cycloserine and oxytocin)for enhancing extinction,effects in clinical trials have been rather disappointing which may reflect the partly contra-indicated effects of the substances(e.g.,potential enhancement of reconsolidation of fear memory or potential side effects).Recent animal models suggest a regulatory role of the renin-angiotensin(RA)system in fear extinction and human studies have also identified an intriguing association between PTSD and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with hypertension.However,whether modulation of the RA system has effects on fear processing in humans remains unclear.Against this background,the present randomized placebo-controlled pharmacologic functional magnetic resonance imaging(fMRI)experiments aimed at(1)determining the extinction enhancing potential of the angiotensin II type 1 receptor antagonist losartan-an approved medication with an excellent safety profile-in humans and systematically examining the potential clinically contraindicated effects of losartan on(2)fear acquisition and(3)fear memory consolidation.Effects of losartan on fear extinction were investigated using a modified Pavlovian fear conditioning and extinction paradigm with concomitant fMRI and psychophysiological threat response(skin conductance response(SCR))acquisition.Specifically,seventy male Chinese subjects underwent a fear conditioning paradigm and were subsequently randomly assigned to losartan(50mg)and placebo treatment groups and the extinction paradigm started 90 minutes after either losartan or placebo administrations.Losartan significantly accelerated the decline of the psychophysiological fear response during early extinction learning.On the neural level,the acceleration was accompanied by fear-specific enhancement of ventromedial prefrontal cortex(vmPFC)activation as well as reduced whole-brain and vmPFC partial conditioned fear signature response in the losartan group during early extinction.Voxel-wise mediation analysis further revealed that the effect of losartan on extinction acceleration required treatment-induced increased vmPFC activation.Moreover,on the network level losartan-accelerated fear reduction during early extinction was paralleled by stronger functional coupling between the vmPFC and the amygdala,specifically the basolateral subregion.Overall,the present results indicate an important regulatory role of the RA system in fear extinction learning in humans.This role is mediated by vmPFC activation and its interaction with the amygdala during confrontation with conditioned fear stimulus.From a clinical perspective,adjunct losartan treatment could represent an innovative strategy to enhance the efficacy of exposure-based interventions.An important consideration relevant to the clinical utility of losartan as a neuroenhancer in exposure therapies is its potential effects on fear acquisition.Specifically,because it functions as an emotional learning enhancer during extinction,losartan might also augment learning of fear-related unspecific experiences during an exposure session via enhancing fear memory acquisition.Therefore,in study 2 we conducted a randomized placebo-controlled pharmacologic experiment while fMRI and psychophysiological fear responses were acquired simultaneously to examine losartan effects on fear acquisition.One hundred and seventeen subjects were randomly assigned to losartan and placebo treatment groups.Ninety minutes later they underwent a modified fear conditioning paradigm with two runs.Both groups exhibited increased SCR to the conditioned fear stimulus as compared to safety signal demonstrating successful acquisition of the fear response.Repeated measures ANOVA revealed no main effect of treatment group or interaction effects on psychophysiological fear responses and direct group comparisons revealed that the two groups exhibited comparable SCR to the conditioned fear stimulus at all learning stages.On the neural level,both groups activated the fear network in response to the conditioned fear stimulus,which further confirmed successful fear acquisition.In line with the psychophysiological findings,repeated measures ANOVA and simple comparisons did not reveal any significant treatment effects on brain activation.These null findings were further confirmed by multivariate conditioned and subjective fear signatures.Overall,the present findings indicate that the RA system blocker losartan has no effects on fear memory acquisition on either psychophysiological or neural levels.Another consideration of the clinical utility of losartan regards its effects on fear memory consolidation.To this end,in study 3,we employed resting-state fMRI(rs-fMRI)to investigate potential effects of losartan on fear memory consolidation.The participants were the same as study 2 and ninety minutes after drug administrations they underwent a 6-minute rs-fMRI scanning(T1),a fear conditioning paradigm and another6-minute rs-fMRI scanning(T2,i.e.,fear memory consolidation)following fear acquisition.Spectral Dynamic Causal Modelling(DCM)was employed to investigated the effective connectivity between dorsal anterior cingulate cortex(dACC;a key node in fear expression)and vmPFC(a key node of fear inhibition).Parametric Empirical Bayes(PEB)analysis revealed a reduced inhibitory influence of the vmPFC on the dACC and itself during fear memory consolidation as compared to resting state before fear acquisition(main effect of time),reflecting fear consolidation effects.With respect to treatment effects,losartan reduced dACC influence on vmPFC and itself and increased inhibitory control of vmPFC on dACC.Moreover,group by time interaction effects were found on dACC to vmPFC and itself as well as vmPFC to dACC effective connectivity.Post hoc comparisons revealed that during T1 losartan decreased the effective connectivity of dACC to itself whereas during T2 losartan decreased the effective connectivity of dACC to vmPFC while increased inhibitory influence of vmPFC to dACC.Together,our results demonstrate that the fear memory consolidation might be characterized by a reduction of inhibitory influence of vmPFC on dACC and itself and that losartan could increase the control ability of vmPFC over dACC,suggesting that losartan may have the potential to attenuate fear memory consolidation on the neural level.In summary,we conducted three fMRI studies to systematically explore the effects of losartan on fear processing.We found that losartan could accelerate fear extinction learning through enhancing vmPFC activation,while it had no effects on fear memory acquisition and might potentially reduce fear memory consolidation by increasing the inhibitory control of vmPFC on dACC.Our findings suggest that adjunct losartan administration has the potential to facilitate the efficacy of exposure-based interventions in anxiety disorders.